Galantamine (I) ((4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) is a known reversible,
competitive acetylcholinesterase inhibitor. The compound can be isolated from the bulbs of the Caucasian snowdrops Galantanus woronowi in addition to the common snowdrop Galanthus Nivalis.
Galantamine and its salts have been employed as a pharmaceutically active agent in the treatment of a variety of disorders, including mania, alcoholism, nicotine dependence, and Alzheimer's disease. In particular, galantamine hydrobromide has been used for the treatment of Alzheimer's disease and is currently formulated as film-coated tablets of 4 milligram (mg), 8 mg, and 12 mg base equivalent doses for twice a day oral administration under the trade name RAZADYNE, as well as hard gelatin extended-release capsules of 8 mg, 16 mg, and 24 mg base equivalent doses for once daily oral administration under the trade name RAZADYNE ER.
As an acetylcholinesterase inhibitor, galantamine is known to be active at nicotinic receptor sites, but not on muscarinic receptor sites. It is capable of passing the blood-brain barrier in humans, and presents no severe side effects in therapeutically effective dosages. Although no severe side effects are found, when first dosed, patients may experience the occurrence of numerous side effects, which affect the patients' tolerability of the drug. Side effects, such as nausea or vomiting and headaches, often occur when the drug is introduced at high doses. An initial therapeutic regimen often starts with first introducing galantamine at low doses for several weeks followed by the gradual increase to the optimal active dose for the patient. When the regular dosing of galantamine is interrupted for two or more days, it is recommended to commence dosing at the lowest levels as continuation at the doses prior to the interruption are generally not well tolerated by the patient. Such side effects may result in lack of patient compliance.
Furthermore, certain patient populations, such as Alzheimer's patients, may find it difficult to adhere to a dosing regimen that requires administration of a formulation several times a day. Accordingly, controlled-release formulations of galantamine are a particularly attractive alternative to immediate-release formulations as they can be administered less frequently and can provide more stable blood levels.
Certain controlled-release galantamine compositions are known (see, for example, WO 00/38686). Such compositions include particles containing galantamine and a water soluble excipient, wherein the particles are coated with a release rate controlling membrane coating. However, further improvements in the area of controlled-release formulations may provide improved pharmacokinetic and/or dissolution profiles not yet achieved by known formulations.
There remains a continued need in the art for improved controlled-release galantamine formulations that can be administered once daily or even less frequently.